5&#39;,6&#39;-dihydro-2h-pyran-4&#39;-yl ethers of estrogenic steroids



United States Patent 21' Claims ABSTRACT OF THE DISCLOSURE The ,6'-dihydro-2H-pyran-4'-yl ethers of estrogen steroids have high oral activities.

This is a continuation-in-part of application Ser. No.

731,301 filed May 22, 1968. V

This invention relates to novel and useful 5',6-dihydro- 2H-pyran-4'-yl ethers of estrogen steroids, the steroid nucleus thus bearing a new group represented by the formula:

Ra I.....R5

wherein R is hydrogen, methyl, methoxy, hydroxyl or conventional hydrolyzable esters thereof; or X 7 R is hydrogen or methyl; and when Z is a single bond, R can 'be alpha or beta oriented;

R is hydrogen, hydroxy or conventional hydrolyzable esters thereof (e.g. lower acyloxy or lower cycloacyloxy groups) when Z is a single bond and is hydrogen when Z is a double bond;

R is hydrogen, a lower alkyl group, such as methyl, ethyl, propyl, and the like, a lower alkenyl group, such as vinyl and the like, or a lower alkynyl (including halo lower alkynyl with a halogen, such as fiuoro, chloro or bromo), such as ethynyl, fiuoroethynyl, chloroethynyl, bromoethynyl, propynyl, trifiuoropropynyl, butynyl, hexynyl, and the like, or

R is methyl or ethyl;

X and X each is hydrogen, hydroxy or conventional hydrolyzable esters thereof, lower alkoxy, lower cycloalkoxy, lower cycloalkenyloxy, tetrahydropyran-Z'-yloxy,

4-(lower)alkoxytetrahydropyran-4-yloxy, or X; or X and-X together can be keto; and at least one of X v and X is X;

Z is a single or double bond.

The preferred estranes are estra-l,3,5(l0)-trienes having 5',6-dihydro-2H-pyran-4-yl ether groups at the C-3, C-17B and C-3,17B positions of the steroidal nucleus. The term estrogen steroids is used herein as denoting estranes having an aromatic A ring, with or without additional unsaturation such as double bonds between the C-7 and C-8 positions of the nucleus.

The terms (lower)alkyl and derivations thereof appearing in the above definitions and elsewhere in the instant specification denote valkyl groups containing from 1 to 6 carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl, and the like.

The term conventional hydrolyzable ester as used herein denotes those hydrolyzable ester groups conventionally employed in the steroid art, preferably those derived from hydrocarbon carboxylic acids or phosphoric acids and their salts. The term hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from 1 to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogeno, and the like, attached to the hydrocarbon backbone chain. Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecanoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate. trimethylacetate, t-butylacetate, trimethylhexanoate, meth ylneopentylacetate, cyclohexylacetate, cyclopentylpropio' nate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-5,j8-dimethylglutarate, acetoxyacetate, 2-chloro-4-nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, fi-chloropropionate, trichloroacetate, B-chlorobutyrate, dihydrogen phosphate, dibenzyl phosphate, benzyl hydrogen phosphate, sodium benzyl phosphate, cyclohexylammonium benzyl phosphate, sodium phenyl phosphate, sodium ethyl phosphate, di-p nitrobenzyl phosphate, sodium o-methoxyphenyl phosphate, cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacyl phosphate, benzyl o-carbomethoxyphenyl phosphate, and the like.

By the term aryl. is included aryl, aralkyl, and alkaryl groups, such as phenyl, p-chlorophenyl, p-methoxyphenyl, benzyl, phenethyl, tolyl, ethylphenyl, and the like. The wavy line (3) designates and includes both the alpha and beta configuration.

The novel 5',6'-dihydro-2H-pyran-4'-yl ethers of this inventionhave high oral anti-fertility and estrogenic activity. These compounds can be used parenterally in the same manner and dosage as estradiol and when administered orally are used in the same manner as ethynylestradiol. The compounds of this invention can be administered in any of the number of conventional pharmaceutical forms, and particularly in ones suited for oral administration, e.g. in solid form, such as in pills, powders, capsules, tablets, or the like, or in liquid form, such as syrups, emulsions, suspensions, and the like.

The preferred compounds of this invention are 176- (5',6-dihydro-2H-pyran-4-yloxy) ethers of estrogenic steroids and particularly the ethers of secondary 17B- hydroxy groups, for example, the 17,6-(5', 6-dihydro-2H- pyran-4'-yloxy) ethers of natural estrogenic compounds,

such=as=estradion;-Priorto this invention, one of the most effective estrogenic agents was estradiol, the natural hormone, but because the agent has a very low oral activity, its use byother than parenteral' routes was impractical. Previously known orally active estrogenic agents are forms of compounds having structures completely different from" estradiol (e.g. ethynylestradiol) and do not provide a natural hormone, such as estradiol, to the body. In

contrast, the orally active 17B-(5,6-dihydro-2H-pyran-- 4-y10xy)estra-1,3',5(l0)-trien-3-0l is a form of the natural hormone estradiol and introduces estradiol into the body when taken orally.

"The novel steroidal 5,6'-dihydro-2H-pyran-4'-yl ethers of this invention are prepared by reacting the steroid nucleus having a reactive hydroxyl group at one or more of the 3 and 175 positions (depending upon the particular steroid nucleus) with an excess of a 4-'-(lower)alkoxy- 5 ',6'-dihydro-2H-pyran, preferably 4-methoxy-5,6-dihydro-ZH-pyran. Free hydroxyl-containing parent compounds which are stable under acidic conditions can be reacted under substantially anhydrous conditions with an excess of the alkoxy dihydropyran in the presence of a small amount of an acidic catalyst, for example, hydrogen chloride, p-toluenesulfonic acid, boron trifluoride etherate, and the like, either alone or together with an inert, organic solvent, such as benzene, diethyl ether, methylene chloride or the like, at a temperature of from 0 C. to about 50 C., and preferably at room temperature (about 25 C.) for from about one to about 72 hours. When the free hydroxyl-containing parent compound is unstable and estra-1,3,5(),7-tetraenes, the reaction is preferably carried out in the presence of a sulfonyl halide rather than one of the above acidic catalysts. For this alternative reaction, any stable sulfonyl halide may be used as the catalyst, especially p-toluenesulfonyl chloride, benzene sulfonyl chloride, p-nitrobenzene sulfonyl chloride, and the like. The reaction is carried out using a large excess 4-yl ether is then isolated in a conventional manner. For

-tion, a second series of ethers corresponding to those represented by Formula I but wherein X is a 4-(lower)- alkoxytetrahydro-4'-yloxy group are also formed. Use of hydrocarbon solvents for the reaction medium, higher catalyst concentrations, and longer reaction times increase the yield of the 5,6-dihydro-2H-pyran-4'-yloxy compounds.

The 4'-(1ower)alkoxy-S',6-dihydro-2H-pyran reactants used to form the ethers of this invention can be prepared by well-known methods. For example, tetrahydro-4-pyrone 1 can be reacted with a primary or secondary lower alkanol under acidic conditions to form the intermediate, 4',5'- di(lower)alkoxytetrahydropyran, which upon distillation with an acid such as toluenesulfonic acid or mesitylenesulfonic acid, yields the 4-(lower)alk0Xy-5,6'-dihydro- -2H-pyran product. Such a method is described by Reese under acidic conditions, such as allylic hydroxy steroidset al., I. Am. Chem. Soc., 89, 3367 (1967). The lower alkanol is preferably methanol but it can be other lower alcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, amyl alcohol, hexanol, and the like, to form the corresponding pyrans such as, for example, 4'methoxy-5 ,6'-dihydro-2H-pyran, 4-ethoxy-5 ',6'-dihydro-ZH-pyran, etc.

The novel estrogen steroid ethers of Formula I can be prepared by processes which can be illustrated schematically as follows:

O 0' Rs R R 1 RI} R; R'1 R1 }z (IV) }z (v) }z (v1) HO X X R2 R2 R2 X Rn |-...R5

"RI: R3 1?.1 I R1 }z (VII) }z (VIII) H0 X 0 OH X Rs H t 's Lm Rn law W Y ".11 R;- R R R I l I 1 l I }z (IX) }z (X) }z (XI) R1O I t R 0 R 0 R2 Rz -L1R2 of the dihydropyran such as, for example, from about In the above formulas, R' is hydrogen, methyl or a ten to 25 parts (mo1ar ratios or parts by weight or conventional hydrolyzable ester group; R is hydrogen or volume) either alone or In the presence of a co-solvent, a conventional hydrolyzable ester group if Z is a single such as benzene, dioxane, diethyl ether, methylene chloride, and the like, in the presence of a catalyticamount of the sulfonyl halide such as, for example, from about 0.001 to 0.1 mole equivalent of sulfonyl halide per mole bond and is hydrogen if Z is a double bond; and R R hereinafter for Formula I. R is an alkyl or cycloalkyl group, preferably methyl or cyclopentyltR is an acyl equivalent of dihydropyran. The 5',6-dihydro-2H-pyrangroup having from 1 to 12 carbons such as acetyl or a lower alkyl or lower cycloalkyl group such as methyl or cyclopentyl; and R is hydroxy or a conventional hydrolyzable ester thereof.

In carrying out the above illustrated process, to form the ether at C-3 (Formula VI), the compounds of Formula IV are reacted with a 4' alkoxy 5,6' dihydro- 2H-pyran in the presence of an acidic catalyst to form the 3 '(5,6' dihydro 2H pyran 4 yloxy) ethers of Formula V. Protecting groups can then be removed from C-l or C-16a-hydroxy groups, if desired. This l7-ketone can then be converted to the corresponding l7a-unsubstituted 175 hydroxy derivative (VI: R =H and R =hydroxy) or to the corresponding 17a '(lower alkyl, lower alkenyl, or lower alkynyl) 17,8 hydroxy derivative (IV: R lower alkyl, lower alkenyl, or lower alkynyl and =R =hydroxy) by conventional methods. When desired, selective esterification or etherification can then be used to form the respective groups from liberated, reactive hydroxyls by conventional procedures.

When the 17tZ-UIlSUbStlt11ted derivatives are desired, the 3 (5,6 dihydro 2H pyran 4' yloxy) 17 one (V) can be dissolved in an inert organic solvent, for example, a lower alkanol, such as methanol, an ether, such as dioxane or tetrahydrofuran, or the like, and reacted under neutral conditions with a metal hydride, for example, lithium aluminum hydride, sodium borohydride, and the like, at a temperature ranging from room temperature to reflux temperature for from about one to 24 hours, thus giving the corresponding 17a unsubstituted 17f? 01 (VI), e.g. 3 (5',6' dihydro 2H pyran 4 yloxy)- 1,3,5(l) estratrien 175 01 (VI: R R and R hydrogen; R methyl; and R =hydroxy). This reaction also cleaves acetoxy groups.

When the 170: (lower)alkyl, (lower)alkenyl or -(lower)alkynyl derivatives are desired, the 3 (5,6 dihydro 2H pyran 4' yloxy) 17 one (V) can be refluxed in thiophene-free benzene under substantially anhydrous conditions, with a lower alkyl, lower alkenyl, or lower alkynyl magnesium halide, such as methyl, vinyl, or ethynyl magnesium bromide, or the like, for about three hours or longer, thus giving the corresponding 17::- (lower alkyl, lower alkenyl, or lower alkynyl) 17/8 01 (VI), e.g. 3 (S,6 dihydro 2H pyran 4' yloxy)- 17oz methyl (vinyl or -ethynyl) estra 1,3,5() trien- 175 01 (VI: R R and R hydrogen; R methyl, vinyl, or ethynyl, respectively; R methyl; and R hydroxy). This reaction also cleaves ester groups in the molecule.

Similarly, 3 (5',6' dihydro 2H pyran 4' yloxy)- 17-one (V) dissolved in absolute diethyl ether can be reacted under an inert nitrogen atmosphere with a lower alkyl, alkenyl, or alkynyl lithium compound, such as ethyl lithium, vinyl lithium, ethynyl lithium, or the like, for 48 hours or longer at room temperature to provide the corresponding 17a (lower alkyl, lower alkenyl, or lower alkynyl) 17/3 01 (VI). The 3 (5',6 dihydro 2H- pyran 4' yloxy) 17 one can also be dissolved in anhydrous benzene containing potassium t-amylate and reacted under an inert nitrogen atmosphere with gaseous acetylene at room temperature for 40 hours or longer to give the corresponding 17a ethynyl 17/3 01 (VI), which can then be hydrogenated in a known manner to give the corresponding 17u-vinyl or 17a-ethyl derivatives.

When the 17cc monohaloalkynyl l7 8-hydroxy derivatives are desired, a 1,2-dihaloethylene, with at least one of the halogens being other than fluorine (such as l-chloro- 2 fluoroethylene, or 1,2 dibromoethylene) dissolved in anhydrous diethyl ether, is slowly admixed at 0 C., under an inert nitrogen atmosphere with a solution of methyl lithium in anhydrous diethyl ether (prepared, for example, by adding lithium to methyl iodide in anhydrous diethyl ether solution under an inert nitrogen atmosphere at about 10 C.). This mixture is then held at room temperature, with stirring, for from about 90 minutes to about 12 hours, following which the steroid ether (VI), such as 3 '(5,6' dihydro 2H pyran 4 yloxy) estra 1,3,5 (10) trien l7 one (V: R R and R hydrogen; R methyl), is slowly added, and this reaction mixture is held at room temperature for from about 12 hours to about 18 hours to give the corresponding 17a-haloethynyl 17 3 01 (VI). When 1 chloro 2 fluoroethylene is used, a 1701 fluoroethynyl substituent is obtained, 1,2 dichloroethylene gives a 171; chloroethynyl substituent and 1,2 dibromoethylene gives a 17cc bromoethynyl substituent.

A 17a-trifluoropropynyl substituent can be introduced by reacting the 3 (5,6 dihydro 2H pyran 4- yloxy) 17 one with trifluoropropynylmagnesium bromide (prepared by reacting trifluoromethyl acetylene with ethylmagnesium bromide under standard Grignard conditions) in an inert organic solvent, preferably a mixture of diethyl ether and tetrahydrofuran or tetrahydropyran, under substantially anhydrous conditions at room temperature for from about 16 hours to about 24 hours or longer.

A 17a (2,2" difluorocyclopropenyl) group can be introduced by reacting the l7a-ethynyl compound, prepared by an above procedure, with sodium chlorodifluoroacetate, for example, in anhydrous diglyme, at 60 C. under an inert atmosphere for about 80 minutes. Conventional hydrolyzable esters at C-17B can be prepared from the 17 8-ols by conventional procedures.

Each of the thus obtained 17oz unsubstituted 175 ols and 17m (lower alkyl, lower alkenyl, or lower allkynyl)- 17fl-ols Corresponding to Formula VI, when reacted with i an excess of 4' (lower)alkoxydihydro 2H pyran in the manner described hereinabove gives the corresponding 3,17 3 bis(5',6' dihydro 2H pyran 4' yloxy) steroid (VIII), for example, 3,1713 bis(5,6' dihydro 2H- pyran 4' yloxy) 17 on ethynylestra 1,3,5 (10) triene (VIII: R R and R =hydrogen; R =ethynyl; and R =methyl).

Alternatively, estrone or its derivatives (IV) can be first converted to the corresponding 17oz unsubstitutedl7/3-hydroxy derivative '(VII: R =hydrogen) or to the corresponding l7u-(lower alkyl, lower alkenyl, or lower alkynyl) 17/3 hydroxy derivative (VII: R =lower alkyl, lower alkenyl, or lower alkynyl) by the above described conventional methods.

Reactive hydroxy groups, if any, present at positions other than C-3 and C-l7fl in the steroid molecule can be protected or converted to desired esters or ethers by selective esterification or etherification by conventional procedures. For example, these groups can be acylated with a molar insufficiency of acetic anhydride to form a mixture of acetoxy compounds from which the desired free hydroxy compounds can be separated by conventional chromatography. Back hydrolysis of the acylated compounds can also be used to free the more reactive hydroxyl groups before chromatographic separation to increase the yield of desired products. The dihydroxy compound (VII) can then be reacted with an excess of the 4-(1ower) alkoxydihydro-ZH-pyran in the presence of suitable catalyst as above described to form the corresponding 3,l7/3-di(5',6'-dihydro-2H-pyran-4'-yloxy) compounds of Formula VIII. For example, estra-1,3,5(l0)-. trien-3-ol-17-one can be refluxed in thiophene-free benzene under substantially anhydrous conditions with ethyl nyl magnesium halide to give the corresponding 17aethynylestra-1,3,5(10)-triene-3,l7;3-diol; this product when reacted with 4-methoxydihydro-2H-pyran, for example, in the presence of p-toluenesulfonic acids forms 3,17,6- bis(5',6 dihydro 2H pyran-4'-yloxy)-17a-ethylnylestra-l,3,5(10)-triene (VIII: R R and R =hydrogen; R =ethynyl; and R =methyl).

Alternatively, estrone or its derivatives of Formula IV can first be etherified at position C3 by conventional techniques. For example, etherification can be accomplished by treating the 3-hydroxy steroid with sodium hydride and then cyclopentyl bromide in benzene with refluxing to form the 3-cyclopentoxy derivative or by reacting the 3-hydroxy steroid in a potassium hydroxide ethanol solution containing dimethyl sulfate followed by neutralization with acetic acid to form the 3-methoxy deriva? tive. The products (IX) can then be converted to the corresponding 17m-unsubstituted-Uri-hydroxy derivative (X: R =hydrogen) or the corresponding 17a (lower alkyl, lower alkenyl, or lower alkynyl)-17B-hydroxy derivative (X: R =lower alkyl, lower alkenyl, or lower alkynyl) by the above described conventional methods.

Alternatively, the 17,8-hydroxy compounds of Formula VII can be acylated to protect free hydroxy groups at C3 and C-16 (if the latter are present) by conventional techniques with back hydrolysis and chromatographic separation of mixed esters when needed. For eX- ample, acylation can be obtained upon treatment with an appropriate acylating agent, such as acetic or other anhydride in pyridine to provide the corresponding acetylated products represented by Formula X.

The 17B-hydroxy compounds represented by Formula X can then be reacted with an excess of 4'-(lower)alkoxydihydro-ZH-pyran in the presence of an acidic catalyst to form the corresponding 17,B-(5',6'-dihydro-2H- pyran-4'-yloxy) steroids represented by Formula XI. For example, estra-1,3,5(1'0)-trien-3-ol-17-one can be etherified to 3-methoxyestra-1,3,5 (')-trien-17-one (IX: R =methyl) reduced with sodium borohydride in aqueous tetrahydrofuran to 3-methoxyestra-1,3,5(10)-trien-17 6-ol (X: R methyl) and reacted with 4-methoxy-5,6-dihydro-2H-pyran to form 3 methoxy-l7p-(5,6'-dihydro-2H-pyran-4-yloxy)- estra 1,3,5(10) triene (XI). Alternatively, estra 1,3,5 (10)-trien-3,17-diol (VII) can be acylated with a molar equivalent of acetic anhydride, forming a mixture of 3-acetoxy and 17fl-acetoxy compounds. The 3-acetoxy component can be separated by conventional chromatography on neutral alumina, for example, and can then be reacted with 4'-ethoxydihydro-2H-pyran, for example, in the presence of an acidic catalyst, such as hydrochloric acid to form the corresponding 3-acetoxy-17/i-(5',6'-dihydro-2H-pyran4-yloxy) -estra-l,3,5 (10)-triene (XI).

The ester groups in the compounds of Formulas V, VI, VIII, and XI can then be hydrolyzed by conventional techniques to convert the ester group(s) to the corresponding hydroxy group(s).

The starting materials used in the above illustrated process are known in the art or can be obtained by methods known in the art.

Referring to Formula IV, l-methyl derivatives of estrone, such as 1-methylestra-1,3,5 (10)-triene-3-ol-17-on have been disclosed in Tetrahedron, 3, 28 (1958). C-1 hydroxy and ester derivatives of estrone and methods for their preparation have been previously described in US. Pat. No. 2,861,086.

Estrone derivatives having C7a methyl groups, such as 7a-methylestra-1,3,5(10)-trien-3-ol-17-one, and methods for their preparation have been described by Kalvoda et al., Helvetica Chimica Acta., 50, 281 (1967).

Estrone derivatives containing hydroxy or ester groups at C16, such as estra-1,3,5(10-triene-3,16u-diol-17-one and the corresponding 16a-esters, such as 16a-acetate, and methods for their preparation have been described by Leeds et al., Am. Soc., 76, 2943 (1954). The corre-. sponding Cl hydroxy substituted compounds, such as estra-l,3,5(10)-triene-1,3,16a-triol-17-one and the respective 1,16a-acetates, and methods for their preparation have been described in US. Pat. No. 3,024,256. Estrone derivatives containing a l-methyl group in combination with a 16a-hydroxy or -ester group, such as l-methylestra-l,3,5(10)-triene-3,l6ot-diol-l7-one, can be prepared 8 from the corresponding l-methylestrone by the method described by Engelfried et a1. Arznelmittelforschung, 11, 25 (1966), page 1518.

Estrone derivatives containing a C18 methyl group, such as l8-methylestra-1,3,5(lO)-trien-3-ol-17-one can be prepared by the procedure described by Smith et al., Experientia, vol. 19, pp. 394-396 (1953).

These and other starting materials represented by Formula IV can be prepared by total synthesis following the procedure described hereinafter.

PREPARATION In the above equation, the 1-vinyl-6-methoxy-l-tetralol and its C3 and C8 substituted counterparts can be prepared from the corresponding 6-methoxytetralone and its C3 and C8 substituted derivatives, all of which are known by the procedure described in articles by Ananchenko et 2.1., Dokladii Akad. Nauk SSSR, 112, 1067 (1957) and Tetrahedron, 18, 1355 (1962).

The Z-methyl (or -ethyl) cyclopentane-1,3-dione represented by Formula B is well known and has been previously described by Smith et al., J. Chem. Soc., page 4472 (1964).

In the above Formulas A, B and C, as well as in formulas appearing hereinafter, R R and R have the meanings described with respect to Formula I hereinabove.

1-vinyl-6-methoxytetralo1 (112 g.) and 2 ethylcyclopentane-1,3-dione g.) are refluxed for six hours in methanol (275 cc.) containing potassium hydroxide (0.3 g.). Most of the methanol is evaporated and ether-benzene (800 cc.; 1:1) is added. The solution is washed successively with water, 5% aqueous sodium hydroxide solution, water and brine, and dried. The product is recrystallized from methanol (180 cc.) to give 2-ethyl-2- (1,2,3,4 tetrahydro 6 methoxynaphth 1 ylidenethyl) cyclopenta-1,3-dione. Concentrated hydrochloric acid (50 cc.) is added with stirring over one minute to the foregoing dione g.) in ethanol (750 cc.) at 50. After stirring for five minutes, warm (50 C.) cyclohexane (one liter) is added followed by water (350 cc.), and stirring continued for five minutes. The aqueous layer is extracted with cyclohexane and the combined organic solutions are washed, dried and evaporated. The residue is dissolved in hot ethanol (200 cc.) containing cyclohexane (20 cc.) and kept at 0 C. for 16 hours. The precipitate is filtered, dried, purified by percolation in cyclohexane-benzene (9:1) through florisil, and recrystallized from ethanol-cyclohexane (10:1) to give the ketone 3-methoxy 18 methylestra 1,3,5 (10),8,14 pentaen- 17-one. This compound (670 g.) in benzene (2.15 1.) containing 2% palladised calcium carbonate (225 g.) is shaken with hydrogen until 57.64 1. have been absorbed 112 minutes). Filtration and evaporation gives a residue which is recrystallized from methanol to give a product (561.1 g.) 3-methoxy 18 methylestra 1,3,5(l0),8 (9)-tetraen-17-one.

The latter compound (16.8 g.) is added in portions with stirring to sodium borohydride (6 g.) in methanol (500 cc.) under reflux. The mixture boils spontaneously. Acetic acid (15 cc.) is added to the cooled solution, most of the solvent is evaporated, water is added, and the mixture is extracted with ethyl acetate,e The product is recrystallized from acetonitrile to give 3 methoxy 18- methylestra 1,3,5(10),'8 tetraen 175 01 (13.8 q.) which is represented by Formula. C above (where R and R =hydrogen; R =ethyl).

Following the above procedure except replacing the 1 vinyl 6 methoxy 1 tetralol with tetralols substituted at the C-3 and C-8 positions, that is, 1-vinyl-3- methyl 6 methoxy 1 tetralol, 1 vinyl 3,8-dimethyl- 6 methoxy 1 -tetralol, 1 vinyl 6 methoxy-8-methyl- 1 tetralol, 1 vinyl 6,8 dimethoxy 1 tetralol and 1 vinyl 3 methyl -'6,8 dimethoxy 1 tetralol, the corresponding C-1 and C-7 substaituted 3-methoxy-18- methylestra 1,3,5(10),8 tetraen 175 -ols are obtained, a '3 methoxy 7,18 dimethylestra 1,3,5 (10),8 tetraen 175 ol, 1,7,18 trimethyl 3 methoxyestra-1,3, (10),8 tetraen 175,-01 1,18 dimethyl 3 methoxyestra 1,3,5(),8 tetraen- 175-01, 1,3 dimethoxy 18- methylestra 1,3',5(10),8 tetraen 175 ol and 1,3-dimethoxy-7,8-dimethylestra-1,3,5 10) 8-tetraen-175-ol.

Similarly by following the above procedures with each of the named or indicated '1-Vinyl-6-methoxy-l-tetralols but replacing the 2 ethylcyclopentane 1,3 dione with 2 methylcyclopentane 1,3 dione, the corresponding 18-unsubstituted estra-1,3,5(10),8-tetraenes are formed, e.g. 3 methoxyestra 1,3,5(10),8 tetrain 175-01, 3- methoxy 7 -methylestra 1,3,5 (10),8 tetraen 175 01, 1,7 dimethyl 3 methoxyestra 1,3,5 (10),8 tetraen- 175-01, 1 methyl 3- methoxyestra 1,3,5(10),8-tetraen- 175-01, 1,3 dimethoxyestra 1,3,5(10,8-tetraen-175-ol and 1,3-dimethoxy 7 rnethylestra-1,3,5(10),8-tetraen- OH O Re v 6 H r IQ In the above Formulas, C and D,- R R and R represent the same groups described with respect to Formula I hereinabove.

Lithium (6 g.) is added'in portions with stirring to 3- methoxy 18 methylestra 1,3,5 (10 ),8 tetraen 175-v 01 (16.8 g.) in liquid ammonia (400 cc.) -aniline (150 cc.) -tetrahydrofuran '(50 cc.). After stirring for two hours, ammonium chloride (50 g.) and then water (600 cc.) are added, and the mixture is extracted with ether. The product, 3 methoxy 18 methylestra 1,-3,5(10) trien-175-o1, is recrystallized from hexane. To this com-. pound (50 g.) in acetone (2 1.) containing anhydrous magnesium sulfate-(60 g.) is added 8 N-chromic acid with stirring. The mixture is stirred for five minutes and pro? pan-2-0l (ZOO-cc.) and sodium hydrogen carbonate (100 g.) are added. The solids are filteredfrom the mixture and washed. with hot chloroform. Evaporation of the combined filtrate and washings give a residue which is percolated in ether through a column of neutral alumina. Recrystallization of the product from methanol gives the ketone 3 methoxy 18 methylestra 1,3,5 (10)-trien- 1'7-one represented by Formula D. Following the same procedure but replacing the 3 methoxy 18 methy1estra 1,3,5 (10),8 tetraen 175-01 with the corresponding compounds wherein R is methyl or. methoxy, R is hydrogen or methyl, and R is methyl or ethyl, the corresponding substituted 3 methoxyestra 1,3,5 (10)-trienl7-ones are produced, e.g.

CHaO- R: CH 0- R2 In Formulas C and E, R R and R represent the same groups as in Formula I.

3-methoxy-l8-methylestra l,3,5(10),8 tetraen-17501 (1 g.) is mixed with a benzene-hexane solution (1:1) of 1.15 equivalents of m-chloro perbenzoic acid at 0 C. The reaction mixture is allowed to stand for five hours at 0 C. and then washed with a sodium bicarbonate solution and water, dried and evaporated, giving a mixture of 3-methoxy-8,9-oxo- 1 8-methylestra-1,3,5 (10)-trien-175- 01 and 3-methoxy 18 methylestra-1,3,5(10),9-tetraene- 8a,175-diol. The mixture is added to a solution of ben zoic acid and chloroform converting the mixture to a pure 3-methoxy-18-methylestra-1,3,5 10) ,9 1l)-tetraene 804,175-di0l. The reaction mixture is washed with sodium carbonate solution and water, dried and evaporated.

A solution of the last named compound (2 g.) in methanol (200' ml.) is added to a suspension of 5% palladium-on-carbon catalyst (0.5 g.) in methanol (50 ml.) which has been hydrogenated for 30 minutes, and hydrogenation with agitation is continued until the uptake of hydrogen has ceased. The catalyst is removed by filtration and the solution is evaporated to yield 3- methoxy 18 methylestra-1,3,5(10)-triene-8u,l75-diol which is recrystallized from methylene chloridezhexane for further purification. This compound (1 g.) is then refluxed with an excess of methanesulfonyl chloride in pyridine until the dehydration is complete. Water is added to the reaction mixture and its extracted with chloroform; the chloroform solution is then evaporated to dryness. Refiltration of the product in benzene through florisil and recrystallization from methanol yields purified 3 methoxyestra-1,3,5( 10) ,7-tetraene-l75-methylsulfonate.

A solution of the last named compound (1 g.) and tetrahydrofuran (50 ml.) is added over a 30 minute (2 ml.). Sodium sulfate is next added and the mixture is filtered; the solid thus collected is washed with hot ethyl acetate. The combined organic solutions are then evaporated to dryness and recrystallized from acetone: hexane to yield 3-methoxy 18 methylestra-1,3,5(lO),7- tetraen-l7B-ol.

To the Grignard reagent from magnesium (51 mg.) and methyliodide (0.16 cc.) in ether (3 cc.) is added this compound, and the mixture is heated in an oil bath at 160 C. for one and one-half hours. The cooled mixture is then treated with dilute acetic acid and ether and the latter is extracted thoroughly with 5% potassium hydroxide solution, yielding l8-methylestra-1,3,5(l0),7 tetraene-3,17fi-diol.

A solution of the last mentioned compound (1 g.) in xylene (30 ml.) and cyclohexanone ml.) is distilled to remove moisture. A solution of aluminum isopropoxide (1 g.) in xylene (5 ml.) is added dropwise over five minutes to the slowly distilling solution, distillation being continued for an additional 45 minutes. The mixture is then cooled and diluted with water, a mixture of water and the solvents being removed by steam distillation. The resulting solid is collected by filtration through Celite diatomaceous earth and dried. This solid is extracted with hot acetone and recrystallized from acetone to yield 18-methylestra 1,3,5 (l0),7 tetraen-3-ol-17-one represented by Formula E above.

Repeating the above procedure except for replacing the 3 methoxy-l8-methylestra-l,3,5(l0),8-tetraen-17 8-ol with the corresponding substituted compounds wherein R is methyl or methoxy, R is hydrogen, ot-methyl or 8- methyl and R is methyl or ethyl, and adjusting the concentrations of reactants to compensate for additional reactive groups (e.g. increasing the concentration of the Grignard reagent to cleave both the C-1 and the C3 methoxy groups to the corresponding hydroxy groups), the corresponding substituted estra-l,3,5( lO),7-tetraenes are produced, for example, 1-methylestra-1,3,5( lO),7- tetraen 3 ol l7 one, 1,7 dimethylestra-1,3,5(lO),7- tetraen- 3 ol 17-one, 1,l8-dimethylestra l,3,5(l0),7- tetraen 3 ol 17 one, 1,7,l8-trimethylestra-l,3,5(l0), 7-tetraen-3-ol-17-one, estra 1,3,5(10),7-tetraene-l,3-diol- 17-one, 7-methylestra 1,3,5 10),7 tctraene-l,3-diol-17- one, 18 methylestra-1,3,5 10) ,7-tetraene-1,3-diol-17-one, 7,18-dimethylestra 1,3,5(10),7 tetraene-l,3-diol-l7-onc and 7,18-dimethylestra-1,3,5( l0) ,7-tetraen-3-ol-17-one.

The invention is further illustrated by the following specific but non-limiting examples.

Example 1 Two milliliters of 4'-methoxy-5',6-dihydro-2H-pyran are added to a solution of l g. of estra-1,3,5(10)-trien-3- ol-17-one in ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of ptoluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for four days and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3-(5,6 '-dihydro-2H-pyran-4'-yloxy) estra-1,3,5 (10)-trien-l7-one which is recrystallized from pentane.

By repeating the above procedures with estra-1,3,5( 10)- trienes having hydrogen, methyl, methoxy or hydrolyz- 12 hydro-2H-pyran yields 1,3-bis-(5',6-dihydro-2H-pyran-4- yloxy) -estra-1,3,S l0) -trien-17-one.

Example 2 Two milliliters of 4'-methoxy-5,6'-dihydro-2H-pyran are added to a solution of 1 g. of estra 1,3,5(10),7- tetraen-3-ol-17-one in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days and is then washed with aqueous sodi? um carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3 (5',6' dihydro-2H-pyran-4'- yloxy) estra 1,3,5 (l0),7-tetraen-17-one which is recrystallized from pentane.

Products having other substituents at C-1, C-7, C-16 and C-18 as described with respect to Formula V are obtained from the corresponding Formula IV compounds by this procedure.

' Example 3 A solution of 1 g. of 3-(5,6 dihydro-2H-pyran-4'- yloxy) estra 1,3,5(l0)-trien-17-one in ml. of tetrahydrofuran is added over a 30 minute period to a stirred suspension of l g. of lithium aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for two hours. To the mixture are cautiously added 5 ml. of ethyl acetate and 2 ml. of water. Sodium sulfate is next added, themixture is filtered and the solid thus collected is washed with hot ethyl acetate.-The combined organic solutions are then evaporated to yield 3-(5', 6-dihydro 2 H pyran-4-yloxy)-estra-1,3,5(10)-trien- 1713-01, which may be further purified through recrystallization from acetonezhexane. I

Following the same procedure but replacing the 3-(5', 6'-dihydro 2H-pyran-4-yloxy -estral ,3,5 10) -trien-17- one with the other estra-1,3,5(10)-trien-17-one products of Examples 1 and 2 having at 4 other lower alkoxy groups such as ethoxy, propoxy, butoxy, hexoxy, and the like; having at C-1 (R' hydrogen, methyl or methoxy; at C-7 (R uor S-methyl when the bond between C-6 and C-7 is a single bond; C-l6 (R' is hydrogen or an ester group such as acetyloxy group; C-18 (R is hydrogen or methyl; and the bond between C-7 and C-8 is a. single or double bond gives the corresponding 175-hydroxy products, e.g. 3 (5',6' dihydro-2H-pyran-4'- yloxy) 70c methylestra-1,3,5(10)-trien-17fi-ol, 3-(5',6'- dihydro 2H pyran-4'-yloxy) 16cc acetyloxyestra- 1,3,5(l0) trien-17,8ol, 3 (5',6'-dihydro-2H-pyran-4'- yloxy)-estra 1,3,5 (l0),7 tetraen-17fi-ol, etc.

Example 4 A solution of one chemical equivalent of 3-(5,6'=dihydro-2H pyran 4 yloxy)-estra-1,3,5(10)-trien-17{3- 01 in 30 ml. of benzene is heated to reflux and about 2 ml. removed by distillation to eliminate moisture. The mixture is cooled to room temperature and two chemical equivalents of sodium hydride are added, followed by the dropwise addition of two chemical equivalents of able ester groups at C1; hydrogen or methyl groups at C-7; hydrogen or ester groups at C-16; and hydrogen or methyl groups at C-18 yields the corresponding etherified products, e.g. 3(5',6-dihydro-2H-pyran-4'-yloxy)- 7a-methylestra-1,3,5 l0)-trien-17-one, 3 (5,6 dihydro- 2H-pyran-4-yloxy) l8 methylestra-l,3,5(l0)-trien-l7- one, 1 methyl-3-(5,6-dihydro-2H-pyran-4-yloxy)-estra- 1,3,5 10)-trien-l7-one, 3 (5,6' dihydro 2H pyran-4'- yloxy)-estra-l,3,5(10)-trien-'l6a-ol-17-one, and the like.

Repeating the above procedure except replacing estra- 1,3,5(l0)-trien-3-ol-17-one with estra 1,3,5(l0) triene- 1,3-diol-17-one and using 4 ml. of 4-methoxy5',6'-dipounds.

cyclopentyl bromide in 10 ml. of benzene over a period of 20 minutes. The mixture is allowed to reflux for 20 hours after which time the precipitate of sodium bromide is removel'by filtration and the organic phase dried and evaporated to yield' 3-(5,6'-dihydro-2H-pyran-4'-yloxy)- 17p cyclopentoxyestra 1,3,5 (10 )-triene WhiCh'iS. further purified upon recrystallization from pentane. Repeating this procedure with other products of Examples 1 and 2 yields the coresponding 17fi-cyclopentoxy com- A mixture of 3 (5 ,6-dihydro 2H -pyran-4' -y1oxy)-. estra 1,3,5(l0)-trien-17B-ol- (0.32 g.) and cyclohexanone diethyl ketal (1.0 ml.) is heated at to C.

for 30 minutes, then to C. for 15 minutes. and

13 in benzene, purified by chromatography on alumina, and recrystallized from a mixture of ether, methanol, and pyridine to give 3 (,6'-dihydro-2H-pyran-4-yloxy)-17,B- 'cyclohexenyloxyestra 1,3,5()-triene. Repeating this 'procedure with other'products of Example 3 yields the corresponding l7fi-cyclehexenyloxy compounds.

Example 5 A mixture of 1 g. of 3 (5',6'-dihydro-2H-pyran 4"- yloxy) estra 1,3,5 (10)-trien-17/8-ol, 4 ml. of pyridine, and 2 ml. of acetic anhydride is allowed to stand at room temperature for hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with Water, and dried to yield 3-(5',6- dihydrO-ZH-pyran 4' yloxy) 17,B-acetoxyestra-1,3,

5(10)-triene which may be further purified through recrystallization from acetonezhexane.

Following the same procedure, esters having hydrogen, methyl or methoxy groups at C-1 (R' hydrogen or methyl groups at 0-7 (R2); vhydrogen, methoxy or hydrolyzable esters at C-l6m (R and hydrogen or methyl groups at C-l8 (R are obtained from the corresponding l7p-hydroxy compounds-produced in Example 3. p 1 i Example 6 To a solution of 5 g. of 3 (5,6'-dihydro-2H-pyran- 4 yloxy) 5 estra l,3,5(l0)-trien-l7{3-ol in 100 ml. of anhydrous benzene are added 1 g. of p-toluenesulfonic acid and 10 ml. of undecenoic anhydride. The mixture is allowed to stand for 24 hours at room temperature and poured with stirring into ice and water. The organic phase is separated, washed with 10% sodium .carbonate solution and with water, dried andjevaporatedto yield 3 (5,6.- dihydro 2 H pyran-4-yloxy) 17fl-undecenoylestra- 1,3,5(1())-triene which is further purified through recrystallization from. etherzhexane. Following the same procedure using other acid anhy- .dr-ides, such as butanoic anhydride, heptanoic anhydride, etc. the corresponding esters having two or more carbons in the ester group are formed, e.g. 3 (5',6'-dihydro-2H- pyran 4' yloxy) 17B-heptanoyloxyestra-1,3,5(l0)- triene, and the like are formed. Similarly, estra-1,3,5 (l0)- trien 173 ols having groups at C-l, C-7, C-l6 and 0-18 as indicated in Formula VI (products of Example 3) are converted to the corresponding l7f3-esters by this procedure. Example 7 A solution of 1 g. of 3-(5,6-dihydro-2H-pyran-4'- yloxy)'-estra-1 ,3,5(l0),7-tetraen-17B-ol' in 60 ml. of anhydrous ether is treated with 7.5 molar equivalents of ethylmagnesium bromide in ether and, after a fewrninutes, with 7.5 molar equivalents of acetyl chloride. The mixture is allowed to standat room temperature for" 15 hours, then diluted with water, and extracted with meth- 'ylene chloride. The extracts are washed with water to neutrality dried and evaporated. The residue is chrojmatographed on neutral alumina, eluting with etherzhexane, to yield 3-(5',6 '-dihydro-2H-pyran-4' yloxy) 17,8- acetoxyestra-l,3,5(lO),7-tetraene which is recrystallized from acetone:hexane.

Following the same procedure using other acid chlorides, estra-l,3,5(10)-trien-17B-ols and/or estra- 1,3,5 (10.),7-tetraen-l7,8-ols having groups at C-l, C-7, C-16 and C-l8 as indicated in'FormulaVI are converted to the corresponding 17/3-esters. I

Example 8 Following the procedures of Example 1 but replacing estra-l,3,5(l0)-trien-3-ol-17-one with 3-(5 ,6-'-dihydro ZH-pyran- -yloxy)-estra-l,3,5(10)-trien-17B- o1, 3,17,6- bi s(5;6-dihydro-2H-pyran-4'-yloxy) estra 1,3,5 l0)- triene is obtained.

Following the procedures of Example Z but replacing 'estra-l,3,5(10),7-tetraen-3-ol-l7-one with 3- (S ',6- dihydro-2H-pyran-4'-yloxy)-estra-l,3,5 {10),7-tetraen 175-01 14 yields the corresponding 3,l7/8-bis(5',6' -dihydro-2H- pyran-4'-yloxy -estral ,3 ,5 l0) ,7-tetraene.

Similarly, other 3,17/8-bis(5,6-dihydro-2H-pyran- 4'- yloxy) ethers are obtained from other 4'-alkoxy-5,6-dihydro-2H-pyrans. Substituting other estra-1,3,5(lO)-trien- 17B-ols and estra-1,3,5(l0),7-tetraen-17,8-ols having sub stituents at Cl, C-7, C-16 and C-l8 as indicated in Formula VI (with reactive hydroxyl groups other than at C-3 and C-17fl being suitably protected) yields the corresponding substituted 3,l7fl-bisethers (compounds of Formula VIII).

Example 9 A solution of 5 g. of 3-(5,6-dihydro-2H-pyran-4'- yloxy)-estra-l,3,5(10)-trien-l7-one in 250 ml. of thiophene-free benzene is treated with an equimolar amount of methylmagnesium bromide in anhydrous ether. The mixture is heated at reflux under anhydrous conditions for three hours, cooled and cautiously treated wtih excess aqueous ammonium chloride solution, This mixture is then extracted with ethyl acetate and there extracts are in turn Washed with water, dried over sodium sulfate, and evaporated to dryness to yield 3-(5',6-dihydro-2H- pyran-4'-yloxy)-l7a-methylestra-1,3,5 10) -trien-l7fi 01 which is recrystallized from methylene chloridezhexane.

Repeating the procedure with other lower alkylmagnesium bromides, such as ethyl magnesium bromide, ropylmagnesium bromide, butylmagnesium bromide, amylmagnesium bromide and hexylmagnesium bromide, yields the corresponding l7a-ethyl, l7a-propyl, 17OL-b1ltyl, 170iamyl and l7a-hexylcompounds. Repeating the procedure with other products of Examples 1 and 2 yields the corresponding l7a-l0wer alkyl compounds.

Example 10 Following the procedure of Example 5 but replacing the methylmagnesium bromide with vinylmagnesium bro mide yields 3-(5,6'-dihydro-2H-pyran 4' yloxy) 17avinylestra-l,3,5 (10)-trien 17B 01. Other lower alkenylmagnesium bromides, such as 1'-pro enyl, 2'-propenyl, .1'-butenyl, 2-butenyl, and the like, magnesium bromides, yield the corresponding lower alkenyl products. Similarly, other products of Examples 1 and 2 yield the corresponding l7a-lower alkenyl compounds by this procedure.

Example 11 To a solution of 1g. of lithium aluminum hydride in 100 ml. of anhydrous tetrahydrofuran is continuously bubbled a'slow current of purified acetylene for one hour. Thereafter, 1 g. of 3-(5,6'-dihydro-2H-pyran-4'-yloxy) estral,3,5(10)-trien-l7-one in 10 m1. of tetrahydrofuran is added and the reaction mixture stirred at room temperature for four hours. Eight milliliters of water are then added and the mixture stirred for 30 minutes. The mixture is then filtered and the organic filtrate evaporated to yield 3-(5,6-dihydro-2H-pyran-4-yloxy) 17m ethynylestra-l,3,5(10)-trien-l7B-ol which is recrystallized from acetone hexane.

- Following the same procedure, 3-(5,6'-dihydro-2H- 'pyran-4-yloxy)-17a-ethynyl-l8 methylestra 1,3,5(10)- trien-l7/3-ol', l-methyl-3-(5',6' dihydro 2H pyran-4- yloxy)-'17o-ethynylestra-l,3,5(10)-trien-l718-ol, 3 (5',6'- dihydro-2H-pyran-4'-yloxy)-7a-methyl-l7a ethynylestra- 1,3,5 10) -trien-l7/3-ol and 3-(5',6-dihydro-2H-pyran-4'- yloxy)-l7a-ethynylestra-1,3,5(10),7-tetraen 17p 01, for example,-are obtained from the corresponding 17-ketones.

Similarly, other l7a-ethynyl-l7fl-ols having groups at Toa refluxing solution of 6.2 g. of 3-(5,6-dihydro-2H- pyran-4-yloxy) 17 ethynyl 17,8 acetoxyestra 1,3,5

15 (10)-triene in 15 ml. of anhydrous digylrne, there is added dropwise over a period of about 80 minutes a. heated (about 60 C.) solution of 20.72 g. of sodium chlorodifluoroacetate in 50 ml. of anhydrous diglyme under nitrogen with stirring. After all the sodium chlorodifluoroacetate is added, the reaction mixture is cooled and filtered. The filtrate is evaporated to dryness to reduced pressure. The residue is dissolved in hexane and chromatographed on 300 g. of Florisil (synthetic magnesium silicate), eluting with hexanezether, to furnish 3-(5', 6'-dihydro-2H-pyran-4 yloxy) 170a (2",2" difluorocyclopropenyl) 1 7/3-acetoxyestra- 1,3 ,5 10') -triene.

Following the same procedure but replacing the 3-(5, 6'-dihydro-2H-pyran 4' yloxy) 17a ethynyl 17 3- acetoxyestra-1,3,5(10) triene With the corresponding compounds having other substituents at C1, C7, C-16 and C18 as described with respect to Formula VI (products of Example 11) yields the corresponding 170c- (2",2"-difiuorocyclopropenyl) products.

Example 13 Following the procedure of Example 7 but replacing 3-(5,6-dihydro-2H-pyran-4'-yloxy) estra 1,3,5(10),7- tetraen-17fi-ol with 3-(5',6'-dihydro-2H-pyran-4'-yloxy)- 17u-ethynylestra-1,3,5(10)-trien 17,8 01 and 3(5,6'- dihydro 2H pyran 4' yloxy) 17a ethynylestra- 1,3,5 (10),7-tetraen-17;8-ol, the corresponding 17fl-acetates are obtained, e.g. 3-(5,6-dihydro-2H-pyran-4' yloxy)- l7a-ethynyl-17,6-acetoxyestra-1,3,5(l0) triene and 3-(5', 6'-dihydro-2H-pyran 4 yloxy) 17a ethynyl 17,8- acetoxyestra-l,3,5 l) ,7-tetraene.

Following the same procedure using other acid chlorides and/or l7 3-ols having groups at C-1, C7, C16 and C-18 as indicated in Formula VI are converted to the corresponding 17fl-esters, e.g. 1,3-bis(',6'-dihydro- 2H-pyran-4'-yloxy)-17a-ethynyl 17,8 acetoxy-estra-1,3, 5(10)-triene, etc. When reactive hydroxyl groups other than at 175 are present, the diacetyl products are obtained with a corresponding molar excess of reactants; the monoacetyl products are formed by using a corresponding molar concentration of reactants and separating the desired products by conventional chromatography from the ester mixture formed.

Example 14 Following the procedures of Example 1 but replacing estra-1,3,5()-trien-3-ol-17-one with 3-(5',6' dihydro- 2H-pyran 4 yloxy)-17u-ethynylestra-1,3,5(10)-trien- 17fi-ol, 3,1718 bis(5',6'-dihydro-2H-pyran-4'-yloxy)-17aethynylestra-1,3,5 10) -triene is obtained.

Following the procedures of Example 2 but replacing estra-1,3,5(10),7-tetraen-3-ol-17-one with 3-(5',6' dihydro-2H-pyran-4'-yloxy)-17 z ethynylestra 1,3,5(10),7- tetraen-17fi-ol yields the corresponding 3,17,6-bis(5',6'- dihydro-2H-pyran-4'-yloxy) -17a-ethyny1estra 1,3,5 10) 7-tetraene.

Substituting other estra-1,3,5(10)-trien 17 3 01s and estra-1,3,5(10),7-tetraen-17B-ols at C-1, C7, 046 and C18 as indicated in Formula VI (products of Examples 3, 4 and 9-11 with reactive hydroxyl groups other than 1 at C17fl suitably protected) yields the corresponding substituted 3,175 bisethers (compounds of Formula VIII).

' Example A solution of 8.5 g. of 1,2-dichloroethylene in 50 ml. of anhydrous ether is added in a dropwise fashion under nitrogen and at 0 C. over a 30 minute period to a stirred solution of 15 ml. of 1.4 N methyl lithium in anhydrous ether. After stirring for an additional 90 minutes at room temperature, a solution of 0.5 g. of 3-(5',6'-dihydro-2H- pyran-4'-yloxy)-estra-1,3,5(10)-trien-17-one in 20 ml. of anhydrous ether is added in a dropwise fashion with stirring over a 15 minute period. Stirring at room temperature is continued for 18 hours and the reaction mixture is then poured into ice water and extracted with ether.

16 These extracts are washed with water, dried over sodium sulfate and concentrated under educed pressure. The residue is chromatographed on alkaline alumina with 8:2 hexanezether to yield 3 (5',6 dihydro-2H-pyran-4'- yloxy)-17a-chloroethynylestra-1,3,5(10)-trien 17B 01 which may be recrystallized from methanol.

By the same procedure but replacing 1,2-dichloroethylene with other halogenated ethylenes, such as 1- chloro-Z-fluoroethylene, 1,2 dibromoethylene, and the like, provide the corresponding compound with a 17mfluoroethynyl substituent or 17a-bromoethynyl substitu ent, respectively.

Following the same procedure but replacing the 3-(5', 6'-dihydro 2H pyran 4' yloxy) estra 1,3,5(l0)- trien-17-one with the corresponding 17-keto compounds having substituents at C1, C7, C-16 and C18 as indicated in Formula V, the corresponding 17a-halo ethylene compounds are obtained. I

Example 16 Following the procedure of Example 3 but replacing 3-(5,6'-dihydro-2H pyran 4' yloxy) estra 1,3,5 (10) trien 17 one with estra 1,3,5(10) trien 3- ol-17-one yields estra-1,3,5(10.)-triene-3,17 diol. By the same procedure, estra-l,3,5(10)-triene-3,l7-diols having hydrogen, methoxy and hydroxy, at C-1; hydrogen or methyl at C7; hydrogen or hydroxy at C-16; and hydrogen or methyl at C-18 are obtained from the corresponding estra-1,3,5(10)-trien-3-ol-17-ones.

Example 17 Following the procedure of Example 1 but replacing estra 1,3,5(1 0) trien 3 o1 l7 one with estra- 1,3,5(10)-triene 3,17 diol and using 4 ml. of the 4"- methoxy-S', -dihydro-2H-pyran instead of 2 ml. yields 3,17fl-bis(5',6'-dihydro-2H-pyran-4'-yloxy) estra 1,3, 5 10) -triene.

Following the procedure of Example 2 but replacing estra-1,3,5(10),7-tetraen-3-ol-17-one with estra-1,3,5(10), 7-tetraen-3,17,B-diol and using 4 ml. of the 4'-methoxy- 5,6'-dihydro-2H-pyran instead of 2 ml. yields 3,17/8-bis (5',6-dihydro 2H pyran 4' yloxy)-estra-1,3,5(10), 7-tetraene.

By the same procedures, 3,17fl-bis(5',6 -dihydro,- 2H- pyran-4-y1oxy) estra 1,3,5(10) trienes and 3,17 8 bis(5',6-dihydro-2H-pyran-4'-yloxy) estra-1,3,5(10),7- tetraenes having hydrogen, methoxy, acetoxy, or other ester groups at C1; hydrogen or methyl at C7; hydrogen, acetoxy or other ester at C16; and hydrogen or methyl at Cl8 are obtained from the corresponding diols. 7

Example 18 Following the procedure of Example 9 but replacing 3-(5, -dihydro 2H pyran 4 yloxy) estra 1,3, 5 10)-trien-17-one with estra- 1,3,5.(10)-trien-3-ol-17-one or estra-1,3,5(10),7-tetraen-3 o1 17 one yields 170 methylestra-1,3,5(10)-triene-3,17p diol and 17a-methy1- estra-1,3,5(10),7-tetraene-3,17/3-diol, respectively.

Substituting these products for estra-1,3,5(10)-triene 3,17B-diol and estra-1,3,5 (10),7-tetraene-3,17B-diol in the process of Example 17 yields 3,17,8-bis(5,6-dihydro-2H- pyran-4-yloxy)-17a methylestra 1,3,5(10")-triene and 3,l 7/3-bis(5',6'-dihydro. 2H pyran 4' yloxy) 17amethylestra-1,3,5 10) ,7-tetraene, respectively. I

Example 19 Following the procedure of Example 10 but replacing 3-(5 ',6 '-d1hydro ZH-pyran 4'-yloxy)-estra 1,3,5(10)- trien-17-one with estra 1,3,5(10)-trien 3-ol-17-one or 17 pounds yields 3,l7fi-bis(5,6'-dihydro 2H-pyran-4-yl oxy)-17a-vinylestra 1,3,5(10)-triene and 3,17fl-bis(5',6'- dihydro 2H-pyran-4-yloxy)-17a-vinylestra 1,3,5 (10) 7-tetraene, respectively.

Example 20 Following the procedure of Example 11 but replacing 3- (5',6'-dihydro 2H-pyran 4'-yloxy)-estra-l,3,5(l0)- tr1en-17-one with estra-1,3,5( 10)-trien 3-ol-17-one or estra-1,3,5(10),7-tetraen 3-ol-17-one yields 17a-ethynylestra 1,3,5(10)-triene 3,17-dio1 and l7u-ethynylestra- 1,3,5 10) ,7-tetraene-3, 17-diol, respectively.

Substituting these products for estra-1,3,5(10)-triene-3, 17-diol and estra-1,3,5(10),7-tetraene 3,17B-diol in the process of Example 17 yields 3,17;3-bis(5',6-dihydro-2H- pyran 4-yloxy)-17a-ethynylestra 1,3,5(10)-triene and 3,17l3-bis(5',6-dihydro-2H-pyran 4'-yloxy)-17a-ethynylestra-l,3,5( 10) ,7-tetraene.

Example 21 Following the procedure of Example 15 but replacing 3-(5',6'-dihydro 2H-pyran-4-yloxy)-estra 1,3,5(10)- trien 17-one with estra-1,3,5(10)-trien 3-ol-17-one or estra-1,3,5(10),7-tetraen 3-ol-17-one yields 17a-chloroethynylestra 1,3,5(10)-triene 3,17-diol and 17a-chloroethynylestra-1,3,5( 10) ,7 -tetraene-3,17 -diol, respectively.

Substituting these products for estra-1,3,5(10)-triene- 3,17,8-diol and estra 1,3,5(10),7tetraene-3,17,B-diol in the procedure of Example 17 yields 3,17B-bis(5',6-dihydro-2H-pyran 4-yloxy)-17a-chloroethynylestra-1,3,5 (10)-triene and 3,17B-bis-(5,6'-dihydro 2H-pyran-4- yloxy) 17ot-chloroethynylestra 1,3,5 (10),7-tetraenes, respectively.

Example 22 Following the procedure of Example 12 but replacing 3-(5,6-dihydro 2H-pyran 4-yloxy) 17a-ethynyl-3, 17,6-diacetoxyestra 1,3,5(10)-triene with 17a-ethynyl- 3,17fi-diacetoxyestra 1,3,5(10)-triene or 17a-ethynyl- 3,17,6' diacetoxyestra 1,3,5(10),7-tetraene yields 170c- (2",2"difluorocyclopropenyl) 3,17B-diacetoxyestra-L3, 5 (10)-triene and 17a-(2",2"-difluorocyclopropenyl) 3, 17l3-diacetoxyestra-1,3,5(10),7-tetraene, respectively.

A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of Water and 2.5 ml. of methanol is added over 30 minutes to a refluxing solution of 1 g. of 17u-(2",2"-difluoro cyclopropenyl)-3,17[3-diacetoxyestra 1,3,5 (10)-triene or 17oc-(2",2" difluorocyclopropenyl) 3,175 diacetoxyestra 1,3,5(10),7-tetraene in 30 ml. of methanol under nitrogen. The solution is refluxed for two hours, cooled, neutralized with acetic acid and concentrated under reduced pressure. After the addition of water, the solid which forms is collected by filtration and dried to yield 17oc-(Z",2" difluorocyclopropenyl) estra 1,3,5(10)- triene 3,17,8-diol or 17a-(2",2"-difluorocyclopropenyl)- estra 1,3,5 (10),7 tetraene 3,17,8-diol, respectively, which is recrystallized from acetone:hexane.

Repeating the procedure of Example 1 but replacing estra l,3,5(l)-trien 3-ol-l7-0ne with 17a-(2",2"-difluorocyclopropenyl) estra 1,3,5 (10)-triene 3,17-diol and using 4 ml. instead of 2 ml. of 4-methoxy-5,6'-dihydro ZH-pyran yields 3,17fl-bis(',6-dihydro 2H- pyran 4'-yloxy) 17a- (2",2"-difluorocyclopropenyl)- estra-1,3,5()-triene.

Repeating the procedure of Example 2 but replacing estra-1,3,5(10),7-tetraen 3-ol-17-one with 17a-(2",2"- difluorocyclopropenyl) estra 1,3,5 (l0),7-tetraene 3, 17fi-diol and using 4 ml. instead of 2 ml. of 4'-methoxy- 5',6'-dihydro 2H-pyran yields 3,17B-bis(5',6'-dihydro- 2H-pyran 4'-yloxy) 17u-(2",2"-difluorocyclopropenyl) estra 1,3,5(10),7-tetraene.

Following the same procedure, other 3,17fi-bis(5,6'- dihydro 2H-pyran 4'-yloxy) 17a-(2,2"-difluorocyclopropenyl)-estratrienes and estratetraenes having groups at C-1, C-7, C-16 and C-18 as indicated in Formula VIII are obtained.

18 Example 23 Following the procedure of Example 4, paragraph 1, but replacing 3-(5',6-dihydro ZH-pyran 4-yloxy)- estra 1,3,5(10)-trien 1713-01 with estra 1,3,5(10)- trien 3-ol-17-one or estra 1,3,5 (10),7-tetraen 3-01-17- one, 3-cyclopentoxyestra 1,3,5(10)-trien-l7-one or 3-cyclopentoxyestra 1,3,5 (10),7-tetraen 17-one are obtained. Repeating this procedure with estratrien 3-01-17- ones having hydrogen, methyl or methoxy groups at C-1; hydrogen or methyl groups at C-7; hydrogen, methoxy or hydrolyzable esters at C-16a; and hydrogen or methyl groups at C18 yields the corresponding 3-cyclopentoxyestratrien- (or -tetraen)-17-ones, e.g. 3-cyclopentoxy-18- methylestra 1,3,5 10)-trien-17-one.

To a refluxing solution of 5 g. of estra-1,3,5(10)-trien- 3-ol-17-one or estra 1,3,5 (10),7-tetraen 3-ol-17-one in 500 ml. of ethanol are added over a 30 minute period 20 ml. of dimethyl sulfate and g. of potassium hydroxide in 50 ml. of Water, 5 ml. portions of each being alternatively added. The mixture is then refluxed for 45 minutes, cooled and poured into ice water. The solid which forms upon neutralization with dilute acetic acid is collected, washed with water and dried to yield 3-methoxyestra l,3,5(10)-trien 17-one and 3-methoxyestra- 1,3,5(10),7-tetraen 17-one, respectively, which is recrystallized from chloroformzmethanol. Following the same procedure, ethers having hydrogen, methyl or methoxy groups at C-1; hydrogen or methyl groups at C-7; hydrogen, methoxy or hydrolyzable ester groups at C 16a; and hydrogen or methyl groups at C18 are obtained from the corresponding 3-hydroxy compounds.

Example 24- Two milliliters of dihydropyran are added to a solution of 1 g. of estra 1,3,5(10)-trien 3-ol-17-one in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield B-tetrahydropyran 2-yloxyestra 1,3,5(10)-trien- 17-one which is recrystallized frompentane.

Two milliliters of dihydropyran are added to a solution of 1 g. of estra-1,3,5(l0),7-tetraen-3-ol-17-one in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane, to yield 3-tetr-ahydropyran-2-yloxyestra1,3,5( 10 ,7-tetraen-17-one which is recrystallized from pentane.

Following the same procedure with substituted estra- 1,3,5(10)-trien-3-ol-17-ones and estra-1,3,5(10),7-tetraen- 3-ol-17-ones having hydrogen, methyl, methoxy or hydrolyzable ester groups at C-1; hydrogen ester groups at C-7; hydrogen, methoxy or hydrolyzable ester groups at C-16a; and hydrogen or methyl groups at C-18 yields the corresponding 3-tetrahydropyranyloxy compounds, e.g. 3- tetrahydropyran 2-yloxy-18-methylestra-1,3,5(10)-trien- 17-one.

'Example 25 Following the procedure of Example 3 but replacing 3 (5,6 dihydro 2H-pyran-4'-yloxy)-estra-1,3,5(10)- trien 17 one with estra-1,3,5(10)-trien-3-ol-17one or estra 1,3,5 (10),7-tetraen-3-ol-17one, estra1,3,5(10) trien- 3,17/3-diol or estra-1,3,5(10),7-tetraen-3,17B-diol, respec tively, are obtained.

Following the same procedure, 3,17 3-diols and S-ether- 17,8-ols having hydrogen, methyl, hydroxy or methoxy at C-1; hydrogen or methyl groups at C-7; hydrogen, ane- 1 9 thoxy or hydroxy at C160L and hydrogen or methyl groups at C-18 are obtained from the corresponding 17- ones, e.g. 18-methylestra-1,3,5( l)-trien-3,175-diol, estra- 1,3,5(10)-trien-3,l6a,l75-tri0l, 7a-methylestra-l,3,5(l0)- trien 3,175-diol, 1-methylestra-1,3,5(10)-trien-3,175-diol, estra 1,3,5(10) trien 1,3,175 triol, 3 methoxyestra- 1,3,5 (10) trien 175-0l, 3-cyclopentoxy-18-methylestra- 1,3,5(10) trien 175-ol, estra-l,3,5(10)-trien-3,175-di0l, 3 tetrahydropyran 2-yloxyestra-1,3,5(10)-trien-175-ol, 3 tetrahydropyran 2 yloxy-18-rnethylestra-1,3,5(10)- trien-175-ol, etc.

Example 26 Repeating the procedure of Example 9 but replacing 3 (5,6 dihydro 2H-pyran-4-yl0xy)-estra-1,3,5(10)- trien 17 one with estra-1,3,5(l0)-trien-3-ol-17-one or estra 1,3,5(),7 tetraen-3-ol-l7-one, 17a-methylestra- 1,3,5(10)-trien-3,175-diol and 17a-methylestra-1,3,5(10), 7-tetraen-3,l75-diol, respectively, are obtained.

Example 27 Repeating the procedure of Example 10 but replacing 3 (5',6' dihydro 2H-pyran-4-yloxy)-estra-1,3,5(10)- trien 17 one with estra-1,3,5(10)-trien-3-ol-17-one or estra 1,3,5(10),7 tetraen 3-ol-17-one, 17a-vinylestra- 1,3,5(10)-trien-3,175-diol and 17u-vinylestra-l,3,5(10),7- tetra-3,175-diol, respectively, are obtained. Similarly, other (17u-1ower) alkenyl derivatives are obtained using the respective lower alkenyl magnesium bromides in the above procedure.

Example 28 Repeating the procedure of Example 11 but replacing 3 (5,6' dihydro 2H-pyran-4'-yl0xy)-estra-l,3,5(10)- trien 17 one with estra-1,3,5(10)-trien-3-ol-l7-one or estra 1,3,5(10),7-tetraen-3-ol-17-one, Hot-ethynylestral,3,5(l0) trien 3,175-diol and 17u-ethynylestra-l,3,5 (10),7-tetraen-3,l75-diol, respectively, are obtained. By the same procedure using as starting materials having hydrogen, methyl or methoxy groups at C-1; ether or hydroxy groups at C-3; hydrogen or methyl groups at C7; hydrogen, methoxy or hydroxy groups at C-16a; and hydrogen or methyl groups at 0-18, the corresponding 17oz ethynyl compounds are obtained, e.g. 17aethynyl l8 methylestra 1,3,5(10)-trien-3,175-diol, 17oz ethynylestra 1,3,5 l0)-trien-3,16u,175-triol, 17aethynylestra 1,3,5 (10) trien-1,3,175-triol, 3-methoxy- 17a ethynylestra 1,3,5(10)-trien-175-o1, 3-cyclopentoxy 17cc ethynyl-18-methylestra-l,3,5(10)-trien-l75- 01, etc.

Example 29 Repeating the procedure of Example but replacing 3 (5,6 dihydro 2H-pyran-4'-yloxy)-estra-1,3,5(l0)- trien 17 one with estra-1,3,5(10)-trien-3-ol-17-one or estra 1,3,5 10),7 tetraen 3 ol-17-one, 17u-chloroethynylestra 1,3,5 (l0)-trien-3,l75-diol and 17x-chloroethynylestra-1,3,5 (10),7-tetraen-3,175-diol are obtained. Repeating the procedure with 3-methoxyestra-1,3,5(10)- trien 175-01 yields 3-methoxy-17u-chloroethyny1estra- 1,3,5(10)-trien-175-ol. Similarly, products having other substituents at C-1, C-7, C16 and 0-18 are obtained from the corresponding substituted 17-ones by this procedure.

Example 30 Repeating the procedure of Example 5 but replacing 3 (5,6 dihydro 2H-pyran-4'-yloxy)-estra-l,3,5(10)- trien 175 01 with 170: ethynylestra 1,3,5(10)-trien- 3,175 diol, 3,175-diacetoxy-17a-ethynylestra-1,3,5(10)- triene is obtained. Following the procedure of Example 7 but replacing 3- 5 ,6'-dihydro-2H-pyran-4-yloxy -estra- 1,3,5 (10),7 tetraen 175 01 with 170: ethynylestra- 1,3,5(l0),7 tetraen 3,175 diol, 3,175-diacetoxy-17aethynylestra-1,3,5( 10) ,7-tetraene is obtained.

Following the procedure of Example 12 but replacing 3 (5',6 dihydro 2H-pyran-4'-yloxy)-17u-ethynyl-175- acetoxyestra 1,3,5 (10) triene with 3,175-diacetoxy- 29 17a ethynylestra 1,3,5 (10)-triene or 3,175-diacetoxy- 17oz ethynylestra 1,3,5(10),7-tetraene, 3,175-diacetoxya (2",2 difluorocyclopropenyl) estra-1,3,5(10)- triene and 3,175 diacetoxy 17a-(2,2"-difiuorocyclopropenyl)-estra-l,3,5(lO),7-tetraene, respectively are obtained.

Repeating these same procedures with the other substituted compounds represented by Formula IV yields. the corresponding C1, C-7, C-16 and C-18 substituted products having 17oz (2",2 difluorocyclopropenyl) groups as described with respect to Formula X.

Example 31 A mixture of 1 g. of estra-1,3,5(10)-triene-3,175-diol, 4 ml. of pyridine and 2 ml. of acetic anhydride is allowed to stand at room temperature for 15 hours. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried. The mixture is chromatographed on neutral alumina, eluting with ether:hexane, to yield 3-acetoxy-estra-1,3,5 (10)-trien-175-ol.

Similarly, C-3 esters having hydrogen, methyl, acyloxy or methoxy groups at C-1; hydrogen or methyl groups at C-7; hydrogen methoxy or hydrolyzable esters of Cl6a; hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkynyl and difluorocyelopropenyl at C-17oc; and hydrogen or methyl groups at C18 are obtained from the corresponding 3,175-dihydr0xy compounds as listed below:

3 -acetoxy-17a- (2",2"-difiuorocyclopropenyl -estra- 1,3,5(10)-trien-175-01,

3 -acetoxy-18-methylestra-1,3,5 (10)-trien-175-ol,

3,16a-diacetoxyestra-L3 ,5 10) -trien- 17 5-01,

3 -acetoxy-17a-ethynylestra-1,3 ,5 10 -trien- -01,

3-acetoxy-17a-ethynyl-18-methylestra-1,3,5(10)-trien- 3,16a-diacetoxy-17u-ethynylestra-1,3,5(10)-trien-175-ol,

3-acetoxy-7a-methylestra-1,3 ,5 (10)-trien-175-ol,

1-methyl-3-acetoxyestra- 1 ,3,5 10 -trien- 175-01,

1 ,3-diacetoxyestra-1,3,5 10 -trien-175-ol,

1,3-diacetoxyl 7a-ethynylestra- 1,3,5 10) -trien- 1 75-01, etc.

To a solution of 5 g. of estra-1,3,5(10)-triene-3,175- diol in 100 ml. of anhydrous benzene are added 1 g. of ptoluenesulfonic acid and 10 ml. of undecenoic anhydride. The mixture is allowed to stand for 24 hours at room temperature and poured with stirring into ice and water. The organic phase is separated, washed with 10% sodium carbonate solution and with water, and dried. The mixture is then chromatographed on neutral alumina, eluting with etherzhexane, to yield 3-undecenoyloxyestra-1,3,5(10)- trien-175-ol. Similarly, estra-1,3,5(10)-triene-3,l75-diols having groups at C-1, C-16, C-l7a and C-18 as indicated in Formula VII are converted to the corresponding 3-esters by this procedure.

A solution of 1 g. of estra-1,3,5(l0),7-tetraene-3-175- diol in 16 ml. of anhydrous ether is treated with 7.5 molar equivalents of ethylmagnesium bromide in ether and, after a few minutes, with 7.5 molar equivalents of acetyl chloride. The mixture is allowed to stand at room temperature for 15 hours, then diluted with water and extracted with methylene chloride. The extracts are washed with water to neutrality, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with ether:hexane, to yield 3-acetoxyestra-1,3,5(10),7-tetraen-175-ol which is recrystallized from acetonezhexane.

A mixture of 2 g. of estra-1,3,5( l0)-triene-3,175-diol in 8 ml. of pyridine and an equivalent molar amount of benzoyl chloride is heated at steam bath temperatures for 30 minutes. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with Water and dried. The mixture is chromatographed on neutral alumina, eluting with etherzhexane, to yield 3-benzoyloxyestra-l,3,5(10)-trien-175-ol which is recrystallized from acetonezhexane. Repeating this procedure with estra- 21 1,3,5 (10),7-tetraene-3,l7B-diol yields 3-benzoyloxyestra- 1,3,5 (10),7-tetraen-17[3-ol. Following the same procedure, estratrien-l7,B-ols and estratetraen-l7B-ols having groups at C-1, C-7, C-16, C-l7a and C-18 as indicated in Formula VII are converted to the corresponding 3-benzoy1oxy compounds.

Example 32 Following the procedure of Example 1 but replacing estra-l,3,5(10)-trien-3-ol-17-one with 3 acetoxyestra- 1,3,5(10)-trien-17-ol, 3-acetoxy-17fi-(5,6'-dihydro 2H- pyran-4'-yloxy) -estra-1,3,5 10 -triene is obtained. Following the procedure of Example 2 but replacing estra-1,3, (10),7 tetraen 3 ol 17 one with 3 acetoxyestra- 1,3,5 (),7-tetraen-17-ol, 3-acetoxy 17/3 (5',6'-dihydro- ZH-pyran 4' yloxy) estra 1,3,5 10),7-tetraene is obtained. Repeating these procedures with 17-hydroxy compounds having acyloxy and ether groups at C-3; hydrogen, methyl, acetoxy or methoxy groups at C-l; hydrogen or methyl groups at C-7; hydrogen, methoxy or hydrolyzable esters at C-16a; hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkenyl and difluorocyclopropenyl groups at C-17oc; and hydrogen or methyl groups at C-18, the corresponding 175-(5',6-dihydro-2H-pyran-4- yloxy) ethers are obtained, e.g.

3-acetoxy-17B- (5,6'-dihydro-2H-pyran-4'-yloxy) -17ot- (2",2"-difluorocyclopropenyl -estra-1,3,5 10) -triene,

3-acetoxy-17fl-(5',6'-dihydro-2H-pyran-4'-yloxy)-18- methylestra-1,3 ,5 10) -triene,

3, 1 6a-diacetoxy-l7f3- (5 ',6'-dihydro-2H-pyran-4'-yloxy) estra-1,3,5(10)-triene,

3-acetoxy-17fi-( 5 ',6'-dihydro-2H-pyran-4'-yloxy) -17ocethynylestra- 1,3,5 (10)-triene,

3-acetoxy-175-(5,6'-dihydro-2H-pyran-4'-yloxy) -17uethynyl-l8-methylestra-1,3,5 (10)-triene,

3,16a-diacetoxy-17fl- (5,6'-dihydro-2H-pyran-4-yloxy) 17 a-ethynylestra-1,3,5 (10)-triene,

3-acetoxy-7a-methyl-17B-(5,6'-dihydro-2H-pyran-4'- yloxy) -estra-1,3,5 10) -triene,

1-methyl-3-acetoxy- 17 8- (5 ',6-dihydro-2H-pyran-4'- yloxy)-estra-1,3,5 (10)-triene,

1,3-diacetoxy-17B-(5,6'-dihydro-2H-pyran-4-yloxy) estra- 1,3,5 10 -triene,

1,3-diacetoxy-17B- (5',6'-dihydro-2H-pyran-4-yloxy) 17a-ethynylestra-1 ,3,5 10 -triene,

3-methoxy-17/i- (5',6'-dihydro-2H-pyran-4-yloxy) -17ocethynylestra-1,3,5 (10)-triene,

3-methoxy-17fi- 5,6-dihydro-2H-pyran-4'-yloxy) -estra- 1,3,5 (10)-triene,

3 -methoxy-17[3-(5',6'-dihydro-2H-pyran-4'-yloxy)-17achloroethynylestra-1,3,5 10) -triene,

3-cyclopentyloxy-17fl- 5,6'-dihydro-2H-pyran-4'-yloxy estra- 1 ,3,5( 10 -triene,

3-cyclopentyloxy-17B- 5 ',6-dihydro-2H-pyran-4'-yloxy) 18-methylestra-l,3 ,5 10 -triene,

3-cyclopentyloxy-1 7/3- 5 ',6'-dihydro-2H-pyran-4'-yloxy) 17 u-ethynylestra-l ,3,5 10 -triene,

3 -cyclopentyloxy-17fi-(5',6'-dihydro-2H-pyran-4'-yloxy) 17ot-ethyny1- 1 S-methylestra- 1,3 ,5 10 -triene,

3-benzoyloxy-17,845,6-dihydro-2H-pyran-4'-yloxy)- estra-1,3,5(10)-triene,

3-tetrahydropyran-2'-yloxy-171i-(5',6-dihydro-2H-pyran- 4'-yloxy)-estra-1,3,5 10 -triene,

3 -tetrahydropyran- -yloxy- 17 B- (5 ,6'-dihydro-2H-pyran- 4'-yloxy)-18-methylestra-1,3,5 10 -triene.

Example 33 A solution of 0.17 g. of potassium hydroxide in 0.2 ml. of water and 2.5 ml. of methanol is added over 30 minutes to a refluxing solution of 1 g. of 3-acetoxy-17fi-(5',6'- dihydro-2H-pyran-4-yloxy)-estra-1,3,5 (10) -triene or 3- acetoxy 17fl-(5,6' dihydro-2H-pyran-4' yloxy) estra- 1,3,5(10),7-tetraene in 30- ml. of methanol under nitrogen. The solution is refluxed for two hours, cooled, neutralized with dilute acetic acid, and concentrated under reduced 22 pressure. After the addition of water, the solid which forms is collected by filtration and dried to yield 17 3- (5',6-dihydro 2H pyran 4 yloxy)-estra-1,3,5(10)- trien-3-ol or 17fl-(5',6' dihydro-2H pyran 4' yloxy)- estra-1,3,5(l0),7-tetraen-3-ol, respectively, which is recrystallized from acetonezhexane.

Repeating this procedure with other acylated products obtained in the procedure of Example 32 yields hydroxy compounds having hydrogen, methyl, methoxy or hydroxy groups at C-l; hydrogen or methyl groups at C-7; hydrogen, methoxy or hydroxy groups at C-16a; and hydrogen or methyl groups at C-18, for example:

1713 (5,6' dihydro 2H pyran 4' yloxy) 18- methylestra-l,3,5 10)-trien-3-ol,

17B (5,6' dihydro 2H pyran 4' yloxy) estra- 1,3,5(10)-triene-3,16u-diol,

17/3 (5,6 dihydro 2H pyran 4' yloxy) 17o:- ethynylestra-l,3,5 10) -trien-3-ol,

17B (5,6' dihydro H pyran 4' yloxy) 17aethynyl- 1 S-methyl-estra- 1,3,5 10) -trien-3-ol,

175 (5',6' dihydro 2H pyran 4 yloxy) 17aethynylestra-1,3 ,5 10) -triene-3 ,1 6oc-di0l,

7oz methyl 175 (5,6 dihydro 2H pyran 4'- yloxy)-estra-1,3,5 10 -trien-3-ol,

1 methyl 17,8 (5,6' dihydro 2H pyran 4'- yloxy)-estra-1,3,5(10)-trien-3-ol,

1 hydroxy 17,3 (5',6 dihydro 2H pyran 4'- yloxy) -estra-1,3,5 10 -trien-3-ol,

17/3 (5,6 dihydro 2H pyran 4' yloxy) 17oz- (2"-2"-difiuorocyclopropenyl)-estra-1,3,5(10)-trien-3-ol,

17,8 (5',6 dihydro 2H pyran 4 yloxy) cchloroethynyl-estra- 1 ,3,5 10)-trien-3-o1, etc.

What is claimed is:

1. A 5, -dihydro-2H-pyran-4'-yl ether of an estra-1,3, 5(10)-triene having at position C-l, a member selected from the group consisting of hydrogen, methyl, methoxy, hydroxy and conventional hydrolyzable esters thereof, and 5,6-dihydro-2H-pyran-4-yloxy; at position C-7, 8, a member selected from the group consisting of a single bond and a double bond; at position C-7, a member selected from the group consisting of hydrogen and methyl, said last named member having either on or 13 configuration when the bond at C-7, 8 is a single bond; at position C-16a when the bond at C-7, 8 is a single bond, a member selected from the group consisting of hydrogen, hydroxy and conventional hydrolyzable esters thereof and when the bond at C-7, 8 is a double bond, hydrogen is at position C-l6a; at position C-17oc, a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower haloalkenyl, lower alkynyl, 2",2"- difiuorocyclopropenyl and in conjunction with C-17fi, keto; at positions C-3 and C-17fi, members selected from the group consisting of hydrogen, hydroxy and conventional hydrolyzable esters thereof, lower alkoxy, lower cycloalkoxy, lower cycloalkenyloxy, tetrahydropyran-2'- yloxy, 4-(lower)alkoxytetrahydropyran-4'-yloxy, and 5, 6-dihydro-2H-pyran-4-yloxy, at least one of said members at said C3 and C17 8 positions being a 5,6'-dihydro-2H-pyran-4'-yloxy group.

2. The steroid ether of claim 1 wherein the ether is 3-(5',6-dihydro 2H pyran 4 yloxy)-estra-1,3,5(10)- trien-17-one.

3. The steroid ether of claim 1 wherein the ether is 3- (5',6'-dihydro 2H pyran-4'-yloxy)-estra-l,3,5(10)-trien-17/8-ol.

4. The steroid ether of claim 1 wherein the ether is 3-(5',6'-dihydro 2H pyran-4'-yloxy)-l7a-ethynylestra- 1,3,5 (10)-trien-17fi-ol.

5. The steroid ether of claim 1 wherein the ether is 3-(5',6'-dihydro 2H pyran-4'-yloxy)-7a-methyl-17aethynylestra-1,3,5(10)-trien-17B-ol.

6. The steroid ether of claim 1 wherein the ether is 3-(5',6'-dihydro 2H pyran-4'-yloxy)-17;8-cyclopentoxyestra-1,3,5 (10)-trien-17/3-ol.

7. The steroid ether of claim 1 wherein the ether is 23 3-(5',6'-dihydro 2H pyran-4'-yloxy)-estra-l,3,5(10), 7-tetraen-l7-one.

8. The steroid ether of claim 1 wherein the ether is 3,17/3-bis(5,6'-dihydro 2H pyran-4-yloxy)-estra-1,3, 5( 10)-triene.

9. The steroid ether of claim 1 wherein the ether is 1,3-bis(5',6'-dihydro 2H pyran-4-y1oxy)-17a-ethynylestral-1,3,5(10)-trien-17fi-ol.

10. The steroid ether of claim 1 wherein the ether is 1,3-bis(5',6'-dihydro 2H pyran-4-yloxy)-17a-ethynyl- 17/3-acetoXyestra-1,3,5 10) -triene.

11. The steroid ether of claim 1 wherein the ether is 17fl-(5',6'-dihydro 2H pyran-4-yloxy)-estra-1,3,5(10)- trien-3-ol.

12. The steroid ether of claim 1 wherein the ether is 17fl-(5,6'-dihydro 2H pyran-4'-yloxy)-18-methylestra- 1,3,5(10)-trien-3-ol.

13. The steroid ether of claim 1 wherein the ether is 3-cyclopentoxy-17fi-(5',6'-dihydro 2H pyran-4-yloxy)- estra-1,3,5(10)-triene.

14. The steroid ether of claim 1 wherein the ether is 3-cyclopentoxy-l7fi-(5',6'-dihydro 2H pyran-4'-yloXy)- 18-methylestra-1,3,5 10') -triene.

15. The steroid ether of claim 1 wherein the ether is 3-acetoxy-17/3-(5',6-dihydr0 2H pyran-4-yloxy)-estra- 1,3,5(10)-triene.

16. The steroid ether of claim 1 wherein the ether is 3-tetrahydropyran-2-yloxy-17,8-(5,6-dihydro 2H pyran-4-yloxy)-estra-1,3,5 10 -triene.

17. The steroid ether of claim 1 wherein the ether is 3-cyclopentoxy-17 6-ethynyl-17,8-(5',6-dihydro 2H pyran-4'-yloxy)-estra-1,3,5(10)-triene.

18. The steroid ether of claim 1 wherein the ether is 3-cyclopentoxy-17a-ethynyl-17,8-(5,6-dihydro 2H pyran-4-yloxy)-18-methylestra-1,3,5(10)-triene.

19. The steroid ether of claim 1 wherein the ether is 1,3-diacetoxy-17a-ethynyl-17,6-(5,6'-dihydro 2H pyran-4'-yloxy)-estra- 1,3,5 10) -triene.

20. The steroid ether of claim 1 wherein the ether is 17a-ethynyl-17p-(5',6'-dihydro 2H pyran-4'-yloxy)- estra-1,3,5(10)-triene-3,16a-dio1.

21. The steroid ether of claim 1 wherein the ether is 17fl-(5,6-dihydro 2H pyran-4-yloxy) estra-l,3,5 (10)- 7-tetraen-3-o1.

References Cited UNITED STATES PATENTS 3,256,273 6/1966 Cross 260-23955 3,290,297- 12/1966 Cross 260239.55 3,294,786 12/1966 Cross et al. 260239.55

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 

